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International Union of Basic and Clinical Pharmacology. XCIV 1521-0081/67/2/338–367$25.00 http://dx.doi.org/10.1124/pr.114.009647 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:338–367, April 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors Jörg Hamann, Gabriela Aust, Demet Araç, Felix B. Engel, Caroline Formstone, Robert Fredriksson, Randy A. Hall, Breanne L. Harty, Christiane Kirchhoff, Barbara Knapp, Arunkumar Krishnan, Ines Liebscher, Hsi-Hsien Lin, David C. Martinelli, Kelly R. Monk, Miriam C. Peeters, Xianhua Piao, Simone Prömel, Torsten Schöneberg, Thue W. Schwartz, Kathleen Singer, Martin Stacey, Yuri A. Ushkaryov, Mario Vallon, Uwe Wolfrum, Mathew W. Wright, Lei Xu, Tobias Langenhan, and Helgi B. Schiöth Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.H.); Department of Surgery, Research Laboratories (G.A), and Institute of Biochemistry (I.L., S.P., T.S.), Medical Faculty, University of Leipzig, Leipzig, Germany; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois (D.A.); Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (F.B.E.); MRC Centre for Developmental Neurobiology, King’s College London, London, United Kingdom (C.F.); Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (R.F., A.K., H.B.S.); Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (R.A.H.); Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri Downloaded from (B.L.H., K.R.M.); Department for Andrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (C.K.); Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University Mainz, Mainz, Germany (B.K., U.W.); Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan (H.-H.L.); Department of Molecular and Cellular Physiology (D.C.M.) and Division of Hematology (M.V.), Stanford University School of Medicine, Stanford, California; Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (M.C.P.); Department of Neuroscience and Pharmacology and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark (M.C.P., T.W.S.); Division of Newborn Medicine, at Open University Library on January 22, 2020 Department of Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts (X.P., K.S.); Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom (M.S.); Medway School of Pharmacy, University of Kent, Chatham, United Kingdom (Y.A.U.); HUGO Gene Nomenclature Committee, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom (M.W.W.); Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York (L.X.); Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany (T.L.) Abstract ...................................................................................339 I. Introduction . ..............................................................................339 II. Recommended Nomenclature. ............................................................340 III. Taxonomy and Evolutionary Origin . ......................................................340 IV. Receptor Terminology......................................................................343 V. Autoproteolytic Processing .................................................................343 VI. Extracellular Interaction Partners . ......................................................344 VII. Signal Transduction .......................................................................346 A. G Protein–Mediated Intracellular Signaling. ..........................................346 B. G Protein–Independent Intracellular Signaling .........................................347 C. Modes of Signaling . ..................................................................347 VIII. Expression. ..............................................................................349 IX. Physiology and Disease . ..................................................................349 A. Molecular and Cellular Functions ......................................................349 1. Cell Size, Shape Control, and Cytoskeleton. .........................................349 2. Planar Cell Polarity. ................................................................352 3. Cell Adhesion and Migration. ......................................................353 4. Cell Cycle, Cell Death, and Differentiation. ..........................................353 J.H., G.A., T.L., and H.B.S. contributed equally to this work. Address correspondence to: Dr. Jörg Hamann, Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. E-mail: [email protected]; or Dr. Helgi B. Schiöth, Unit of Functional Pharmacology, Department of Neuroscience, Uppsala University, Husargatan 3, 751 24 Uppsala, Sweden. E-mail: [email protected] NC-IUPHAR is supported in part by Wellcome Trust Grant 099156/Z/12/Z. dx.doi.org/10.1124/pr.114.009647. 338 Adhesion G Protein–Coupled Receptors 339 B. Organ Systems. ........................................................................354 1. Hematopoietic System and Immunity................................................354 2. Cardiovascular System. ............................................................354 3. Respiratory Tract. ..................................................................355 4. Gastrointestinal Tract. ............................................................355 5. Urinary System (Kidney, Urinary Bladder). .........................................356 6. Endocrine System and Metabolism. ................................................356 7. Reproductive Organs. ............................................................356 8. Skeletal Muscle and Bone. ..........................................................356 9. Skin (Including Hair, Nails, and Mammary Gland).. ...............................356 10. Nervous System and Behavior. ......................................................357 11. Sensory Organs. ..................................................................358 C. Clinical Aspects ........................................................................358 1. Developmental Defects. ............................................................358 2. Tumorigenesis.......................................................................359 X. Perspectives on Pharmacological Opportunities . ..........................................360 Acknowledgments. ........................................................................361 References . ..............................................................................361 Abstract——The Adhesion family forms a large ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 branch of the pharmacologically important super- (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), family of G protein–coupled receptors (GPCRs). As ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), Adhesion GPCRs increasingly receive attention from ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 a wide spectrum of biomedical fields, the Adhesion (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, GPCR Consortium, together with the International Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, Union of Basic and Clinical Pharmacology Committee HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), on Receptor Nomenclature and Drug Classification, ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 proposes a unified nomenclature for Adhesion GPCRs. (GPR128), ADGRL1(latrophilin-1,CIRL-1,CL1),ADGRL2 The new names have ADGR as common dominator (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, followed by a letter and a number to denote each CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 subfamily and subtype, respectively. The new names, (VLGR1, GPR98). This review covers all major with old and alternative names within parentheses, are: biologic aspects of Adhesion GPCRs, including ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 evolutionary origins, interaction partners, signaling, (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 expression, physiologic functions, and therapeutic (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), potential. I. Introduction is in contrast to the Secretin GPCRs, which are not au- tocatalytically processed and often mediate hormonal Gprotein–coupled receptors (GPCRs) consist of five main families in mammals, the largest being the responses. Different groups of researchers commonly studying Rhodopsin family, or class A, with about 284 members (plus about 380 olfactory receptors) in humans, followed the Adhesion GPCRs with epidermal growth factor by the Adhesion GPCR family with 33 members, and then (EGF) domains within their N termini started a series the Glutamate family (class C), Secretin family (class B), of workshops that was the foundation for the current and Frizzled family, with 22, 15, and 11 members, larger Adhesion GPCR Consortium (http://www. respectively (Civelli et al., 2013). Originally, it was adhesiongpcr.org/) and the biennial Adhesion GPCR suggested that the Adhesion GPCRs belong to class B Workshops (e.g.,
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